1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5β-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide (rocuronium bromide) of formula I, has the following structure:
with a formula of C32H53BrN2O4 and a molecular weight of 609.70. Rocuronium bromide is used as a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium.
Rocuronium bromide of formula I is marketed under the name ZEMURON® and is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only.
The preparation of rocuronium bromide is disclosed in U.S. Pat. Nos. 5,817,803 and 4,894,369, and in U.S. publication No. 2005/0159398.
U.S. Pat. No. 4,894,369 (“'369 patent”) discloses the preparation of Rocuronium bromide via 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17β-ol of formula II:
wherein R3 is C, N—CH3 or a direct C—C bond. The yield is modest (around 60% w/w yield). The patent discloses the reaction of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17β-ol with morpholine in the presence of water to yield 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol. The step is conducted for a reaction time of three days after which the solvents are removed by evaporation and the final product is crystallized from acetone followed by further recrystallization from methanol.
Thereafter, 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol is reacted with an acetylating reagent to obtain 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α-ol, 17β-acetate. In this acetylation process the product is obtained in low yields of about 48%, comprising a process of purifying from the remaining starting diol, and diacetate side product, by column chromatography followed by crystallization from a mixture of diethyl ether and n-hexane. See '369 patent, col. 5, 11. 31-50 (example 7).
Finally, the mono-quaternary ammonium compound, rocuronium bromide, is prepared by a reaction of the monoacetate derivative and a large excess of allyl bromide (8.7 equivalents) in a pressure bottle at room temperature for 22 hours. See id. at col. 8, 11. 27-46 (example 23). The product is purified by column chromatography on alumina and the combined pure fractions are subsequently crystallized from dichloromethane-diethylether to yield pure rocuronium bromide.
U.S. publication No. 2005/0159398 (“'398 publication”) discloses the preparation of a derivative of Rocuronium through a bis-acetylated intermediate. The bis-acetylated compound undergoes a selective de-acetylation reaction to give a mono-acetate product, which is further purified by two crystallizations to give the desired product in yields of about 52%. See '398 publication, p. 8, ¶¶ 112-115.
Each purification step reduces yield, increases the cost of production, and increases manufacturing time. Thus, processes that reduce cost and manufacturing time, while concurrently increasing the product yield and purity are highly desirable. Also desirable, are processes that simplify the production process. The process of the present invention addresses these shortcomings of the prior art.